Photodynamic therapy, hereinafter also referred to as “PDT”, is a process for treating cancer wherein visible light is used to activate a substance, such as a dye or drug, which then attacks, through one or more photochemical reactions, the tumor tissue thereby producing a cell-killing, or cytotoxic, effect. It has been discovered that when certain non-toxic photodynamic sensitizers, such as hematoporphyrin derivative (“HpD” or “Photofrin® I”) are applied to the human or animal body, they are selectively retained by the cancerous tissue while being eliminated by the healthy tissue.
The tumor or cancerous tissue containing the photosensitizer can then be exposed to therapeutic light of an appropriate wavelength and at a specific intensity for activation. The light can be directly applied through the skin to the cancerous area from a conventional light source (e.g., laser, sun lamp, white light sources with appropriate filters, etc.), or in cases where the cancerous tissue is located deeper within the body, through surgical or non-surgical entry such as by the use of fiber optic illumination systems, including flexible fiber optic catheters, endoscopic devices, etc. The light energy and the photosensitizer cause a photochemical reaction which kills the cell in which the photosensitizer resides.
Although the exact mechanisms of the photochemical reactions that kill the cancer cells are not clearly understood and vary depending upon the type of photosensitizer utilized, what is clear is that photodynamic therapy is effective for the preferential destruction of cancerous tissue. Furthermore, photodynamic therapy has several attractive features over conventional methods for treating cancer such as chemotherapy, radiation, surgical procedures, etc., in that the photosensitizers utilized are generally non-toxic, concentrate or remain preferentially in cancer cells, can be utilized with other modes of treatment since PDT does not generally interfere with other chemicals or processes, etc.
Considerable attention has recently been directed to a group of compounds having the phthalocyanine ring system. These compounds, called phthalocyanines, hereinafter also abbreviated as “Pc”, are a group of photoactive dyes that are somewhat structurally similar (i.e., have a nitrogen-containing ring structure) to the porphyrin family. Phthalocyanines are azaporphyrins consisting of four benzoindole nuclei connected by nitrogen bridges in a 16-membered ring of alternating carbon and nitrogen atoms around a central metal atom (i.e., C32H16N8M) which form stable chelates with metal cations. In these compounds, the ring center is occupied by a metal ion (such as a diamagnetic or a paramagnetic ion) that may, depending on the ion, carry one or two simple ligands. In addition, the ring periphery may be either unsubstituted or substituted.
Since E. Ben-Hur and I. Rosenthal disclosed the potential use of phthalocyanines as photosensitizers in 1985 (E. Ben-Hur and I. Rosenthal Int. J. Radiat. Biol. 47, 145-147, 1985), a great deal of research has followed producing a number of phthalocyanines for photodynamic therapy. Although prior studies with phthalocyanines have been generally disappointing, primarily because of the poor solubility characteristics of the basic ring, some of these compounds have attractive characteristics (C. M. Allen, W. M. Sharman, and J. E. van Lier, J. Porphyrins Phthalocyanines 5: 161-169, 2001; E. Ben-Hur and W.-S. Chan, Phthalocyanines in photobiology and their medical applications. In: The Porphyrin Handbook (K. M. Kadish, K. M. Smith, and R. Guilard, Eds.), vol. 19, Applications of Phthalocyanines, Elsevier Science, pp. 1-35 (2003)).
For example, unlike some of the porphyrin compounds, phthalocyanines strongly absorb clinically useful red light with absorption peaks falling between about 600 and 810 nm (Abernathy, Chad D., Anderson, Robert E., Kooistra, Kimberly L., and Laws, Edward R., Neurosurgery, Vol. 21, No. 4, pp. 468-473, 1987). Although porphyrins absorb light poorly in this wavelength region, as a result of the increased transparency of biological tissues at longer wavelengths, red light is normally used for photodynamic therapy. Thus, the greater absorption of red light by the phthalocyanines over porphyrins allows deeper potential penetration with the phthalocyanines in photodynamic treatment processes.
In addition, the phthalocyanines offer many benefits over the porphyrin components as photosensitizers in that the phthalocyanines are relatively easy to synthesize, purify, and characterize in contrast to the porphyrins, which are often difficult to prepare. Similarly, the metal phthalocyanines are exceptionally stable compounds in comparison to the porphyrin or porphyrin-like compounds. As a result, certain metallic phthalocyanines, such as aluminum phthalocyanine tetrasulfonate (AlPcS) and chloroaluminum phthalocyanine (AlPcCl), offer a number of advantages over porphyrins as therapeutic agents for photodynamic therapy.
Still, there remains a need for a convenient formulation of a photosensitizer that avoids potential toxicity to neighboring healthy tissue.